In this revised PPG, we propose to analyze the function of a new family of genes that we have recently discovered called TIM (T cell Immunoglobulin and Mucin domain containing molecules), which was initially shown to be expressed in T cells and play a crucial role in regulating immunity and tolerance. However, recent data suggests that TIM molecules are not only expressed on T cells but also expressed on antigen presenting cells (APC) in the peripheral immune compartment and in target tissues. The role of TIM molecules in regulating the function of T cells vs. APCs is not well understood. Preliminary data suggest that the TIM family of molecules can positively or negatively costimulate T cell activation and also promote APC activation. Based on these observations, we hypothesize that this family of molecules may have a very important role in regulating both innate and adaptive immune systems and could be exploited in a number of diseases and inflammatory conditions, including autoimmunity, asthma, transplant rejection and tumor immunity. This PPG brings together 3 research projects and 3 cores, involving 11 independent investigators, to address the role of the TIM family of molecules in autoimmunity and transplant rejection. The proposed studies will utilize and examine animal models and human disease conditions. The three projects are highly interdependent and address a common theme: What is the role of the TIM family of molecules in regulating immunity and tolerance? The main themes of the three projects are: 1. The roles of the TIM family of genes in regulating autoimmune T cell responses in mouse models (Project I: Vijay Kuchroo and Joan Goverman, PIs); 2. TIM- 3 regulation of immune responses in the CNS in humans (Project II: David Hafler, David Anderson and Larry Kane PIs); 3. TIM proteins in regulation of transplantation tolerance (Project III: Terry Strom, Wenda Gao and Larry Kane PI). To understand the mechanism by which TIM protein mediate their function in adaptive and innate immune system, in the revised grant we have included a new co-PI (Larry Kane) on projects 2 and 3 to analyze the signaling pathways induced by TIM molecules. The three cores (Administrative, Antibody/lg- fusion protein, Transgenic/Knock-out core) will support these three projects and provide tools that will be shared by all the projects, thus accelerating discovery in an efficient and cost effective manner. Lay Summary: By sharing a set of common set of standardized reagents and information, and conducting complementary experiments in animal models and humans and among different types of inflammatory diseases, the PPG will build a comprehensive understanding of the role of the TIM family of genes in regulation of immunity and tolerance with the potential of exploiting this pathway for therapeutic purposes in humans.